Effects of GLP-1 analogs on metabolic alterations including male sexual function, hypogonadism and erectile dysfunction: a narrative review.

Adenosine triphosphate (ATP) is the main energy substance that ensures physiological and biochemical processes in cells of various natures (; ). Although neurons use energy for protein and lipid synthesis, a significant portion of the energy budget is consumed by ensuring the trafficking of subcellular organelles and the homeostatic mechanisms of network activity (; ; ). Preliminary calculations on the distribution of ATP consumption across various structures and mechanisms that contribute to synaptic transmission have revealed that the restoration of ion homeostasis by transport ATPases and the generation of postsynaptic responses consumes most of the energy at excitatory synapses (; ; ). It has been hypothesized that, in contrast to excitatory synapses, inhibitory synapses do not significantly consume energy because of the proximity of chloride ion (Cl) reversal to the resting membrane potential (). In particular, the calculations demonstrated that inhibitory synapses use energy indirectly, namely, via the activity of secondary-active chloride transport systems (CCCs) and subsequently via Na, K ATPase activity, thereby contributing to the recovery of ion homeostasis in neurons (; ; ). However, in these research disregards the fact that the driving force (DF) for Cl is augmented by excitatory input and that the resulting “shunting” inhibition engenders Cl inflow (). Furthermore, evidence has shown that network activity is accompanied not only by an increase in the intracellular chloride concentration ([Cl]) but also by a decrease in the neuronal pH (pH) and a reduction in the ATP concentration ([ATP]) (; ). Energy use by excitatory neurons. Energy is delivered to the brain as oxygen (O) and glucose from blood vessels. This figure shows a microcircuit in which an axonal input activates by action potentials an excitatory synapse onto an output cell. Figure shows pre- and postsynaptic terminals of excitatory synapse as well as astrocyte. The release of glutamate (Glu) from synaptic vesicles into the synaptic cleft evokes a brief change in the concentration of Glu, which diffuses out of the cleft in to surrounding regions and activates low-affinity AMPA receptors and high-affinity NMDA receptors of the postsynaptic terminal. The astrocyte Glu transporters (EAAT1 and EAAT2) maintain the concentration at a low level. The Glu is then converted into glutamine (Gln) by glutamine synthetase (GS). Astrocytes excrete Gln back into the extracellular media through the Na driven SNAT3 transporter, which is taken up bu an as yet unconfirmed neuronal Gln transporter of the presynaptic terminal. Neurons convert Gln to Glu via a phosphate-activated glutaminase (PAG) reaction to replenish their vesicular Glu stores. Glucose is transported into neurons primarily by the Glut 3 transporter. ATP is supplied to presynaptic and postsynaptic terminals via glycolysis in the cytosol and oxidative phosphorylation in mitochondria. Structures that consume energy at excitatory synapses include (i) presynaptically after Ca entry via voltage-gated Ca-channels to trigger vesicle release, pumping of neurotransmitter into vesicles, and on the vesicle cycle and HATPase involvement; (ii) pumping Na and K by Na, KATPase, and Ca by CaATPase to restore ion gradients postsynaptically after ion entry via AMPA and NMDA receptors and Ca release from internal stores; (iii) in axons after action potentials (APs); (iv) in astrocytes to power the glutamate–glutamine cycle; and (v) in actin/myosin function–ATP is bound and hydrolyzed by the myosin head, breaking the bond between myosin and actin. The energy released cocks the myosin head into a “high-energy” position, ready to bind to actin again (). Relative energy expenditure in presynaptic and postsynaptic terminals as well as during spiking (; ). Comparative analysis of energy consumption in dendrites, axons and glia in the original version () and in the revised version (). Comparative analysis of ATP expenditure by action potentials, synaptic transmission, neuronal and glial resting potential. Structures that consume ATP by inhibitory signaling. This figure shows a microcircuit in which inhibitory neuron’s axon fires and releases neurotransmitters at a synapse. Depending on the target cell, the GABA receptors can mediate inhibition or excitation depending on the [Cl]. Glutamine (Gln) is released by the astrocyte via SNAT3 transporter and is further imported by SNAT1/2 into the GABAergic neuron, where it is metabolized to glutamic acid (Glu) by glutaminases GLS1/2. GAD67/65 converts Glu into GABA (blue circles), which is then loaded into the synaptic vesicles (SV) by VGAT, trafficked to the presynaptic membrane, and released into the synaptic cleft. Once released, GABA interacts with GABARs, activating Cl influx into neuron. The excess of GABA is taken up by the astrocyte via GAT1/3, which simultaneously translocates 2 Na and one Cl. In the astrocyte, GABA is sequentially catabolized by GABA tra